Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis

Bin Zhang (), Dandan Zhao, Fang Chen, David Frankhouser, Huafeng Wang, Khyatiben V. Pathak, Lei Dong, Anakaren Torres, Krystine Garcia-Mansfield, Yi Zhang, Dinh Hoa Hoang, Min-Hsuan Chen, Shu Tao, Hyejin Cho, Yong Liang, Danilo Perrotti, Sergio Branciamore, Russell Rockne, Xiwei Wu, Lucy Ghoda, Ling Li, Jie Jin, Jianjun Chen, Jianhua Yu, Michael A. Caligiuri, Ya-Huei Kuo, Mark Boldin, Rui Su, Piotr Swiderski, Marcin Kortylewski, Patrick Pirrotte, Le Xuan Truong Nguyen () and Guido Marcucci ()
Additional contact information
Bin Zhang: City of Hope Medical Center and Beckman Research Institute
Dandan Zhao: City of Hope Medical Center and Beckman Research Institute
Fang Chen: City of Hope Medical Center and Beckman Research Institute
David Frankhouser: City of Hope Medical Center and Beckman Research Institute
Huafeng Wang: City of Hope Medical Center and Beckman Research Institute
Khyatiben V. Pathak: Cancer & Cell Biology Division, Translational Genomics Research Institute
Lei Dong: Beckman Research Institute of City of Hope
Anakaren Torres: Cancer & Cell Biology Division, Translational Genomics Research Institute
Krystine Garcia-Mansfield: Cancer & Cell Biology Division, Translational Genomics Research Institute
Yi Zhang: City of Hope Medical Center and Beckman Research Institute
Dinh Hoa Hoang: City of Hope Medical Center and Beckman Research Institute
Min-Hsuan Chen: City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute
Shu Tao: City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute
Hyejin Cho: City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute
Yong Liang: DNA/RNA Peptide Shared Resources, Beckman Research Institute
Danilo Perrotti: University of Maryland School of Medicine Baltimore
Sergio Branciamore: City of Hope Medical Center and Beckman Research Institute
Russell Rockne: City of Hope Medical Center and Beckman Research Institute
Xiwei Wu: City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute
Lucy Ghoda: City of Hope Medical Center and Beckman Research Institute
Ling Li: City of Hope Medical Center and Beckman Research Institute
Jie Jin: Zhejiang University
Jianjun Chen: Beckman Research Institute of City of Hope
Jianhua Yu: City of Hope National Medical Center
Michael A. Caligiuri: City of Hope National Medical Center
Ya-Huei Kuo: City of Hope Medical Center and Beckman Research Institute
Mark Boldin: Beckman Research Institute of City of Hope
Rui Su: Beckman Research Institute of City of Hope
Piotr Swiderski: DNA/RNA Peptide Shared Resources, Beckman Research Institute
Marcin Kortylewski: Beckman Research Institute
Patrick Pirrotte: Cancer & Cell Biology Division, Translational Genomics Research Institute
Le Xuan Truong Nguyen: City of Hope Medical Center and Beckman Research Institute
Guido Marcucci: City of Hope Medical Center and Beckman Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38− blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142−/−BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142−/−BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of “bulk” and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142−/−BCR-ABL mice and patient-derived xenografts.

Date: 2023
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DOI: 10.1038/s41467-023-41167-z

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